Regular
readers of this blog will see that there is an underlying logic behind recent
posts. We know levels of the cytokine
IL-6 are raised in autism and we know that high levels of IL-6 in mice produces
a baby with autism and we know this can be reversed by giving IL-6 antibodies
to the mother, prior to birth.
We also know
from numerous previous posts that growth hormone (GH) and the growth factor
IGF-1 are implicated in autism. Both GH
and IGF-1 are used in clinical trials for autism.
Today’s post
draws all this together. It turns out
that IL-6 disrupts the GH-IGF-1 axis.
The hormone GH is supposed to control the release of IGF-1; so a little
more GH should produce a little more IGF-1.
The problem is that the cytokine IL-6 disrupts this relationship. In the presence of elevated amounts of IL-6,
which is characteristic of autism, and regressive autism in particular, GH does
not produce the expected increase in IGF-1; IGF-1 levels are actually reduced.
This is very
important.
A great deal
of money is being spent researching and developing IGF-1 based therapies for
autism and Retts syndrome. Perhaps a
much better strategy would be to clear the disruption from the GH-IGF-1 axis,
so that IGF-1 levels could be restored naturally.
This means reducing IL-6 levels and IL-6 mediated disruption. We already
know how to do this, from previous posts.
Now for some
supporting evidence:-
In the
following study, IL-6 was given to healthy volunteers and the over the next 8
hours their levels of GH and IGF-1 were measured.
The study confirmed earlier
observations that IL-6 infusion leads to increased circulating GH. Despite the
increase in GH levels, the study demonstrated an IL-6 infusion-associated reduction in IGF-I.
Coming back
to mice being given IL-6 to produce autistic pups, Autism Speaks funded a very thorough
post-doctoral study at Caltech that focused on understanding this very issue
(in mice at least). The study aimed to
find out how IL-6 ends up causing autism.
The conclusion is very interesting and again comes back to endocrine
changes and the disrupted GH-IGF-1 axis.
I rest my
case.
"Activation of the maternal immune system in rodent models sets in
motion a cascade of molecular pathways that ultimately result in autism- and schizophrenia-related
behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial
mediator of these effects led us to examine the mechanism by which this cytokine
influences fetal development in vivo. Here we focus on the placenta as the site of direct interaction between
mother and fetus and as a principal modulator of fetal development. We find
that maternal immune activation (MIA) with a viral mimic, synthetic
double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as
maternally-derived IL-6 protein in the placenta. Placentas from MIA mothers
exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK
cells, indicating elevated early immune activation. Maternally-derived IL-6
mediates activation of the JAK/STAT3 pathway specifically in the pongiotrophoblast layer of the placenta, which
results in expression of acute phase genes. Importantly, this parallels an
IL-6-dependent disruption of the growth hormone-insulin-like growth factor
(GHIGF) axis that is characterized by decreased GH, IGFI and IGFBP3 levels. In
addition, we observe an IL-6-dependent induction in pro-lactin-like protein-K
(PLP-K) expression as well as MIA-related alterations in other placental
endocrine factors. Together, these IL-6-mediated effects of MIA on the placenta
represent an indirect mechanism by which MIA can alter fetal development.
Furthermore, we find an IL-6-dependent dysregulation of the GH-IGF
axis in MIA placentas, characterized by decreased levels of GH and IGFI mRNA,
with corresponding decreases in placental IGFI and IGFBP3 protein. The actions
of GH are achieved through the stimulation of IGFI production in target
tissues. In addition, GH regulates the activity of IGFI by altering the
production of either facilitatory or inhibitory binding proteins, including the
IGFI stabilizing protein, IGFBP3. This suggests that the decreased GH levels
seen in MIA placentas leads to the observed downstream suppression of IGFBP3
and IGFI production. It is believed that IGFs in the maternal circulation do
not enter the placenta, and therefore IGFs in the
placenta are derived from the placental compartment itself We demonstrate that
the changes in IGFI and IGFBP3 expression are mediated by IL-6. However, it is
unclear whether decreases in placental GH and subsequent effects on IGF
production are downstream of IL-6-specific STAT3 activation. IL-6 does modulate
IGFI and IGFBPs in several tissues, including placenta and cord blood.
Pro-inflammatory cytokines, including IL-6, decrease circulating and tissue
concentrations of GH and IGFI. We observe that IL-6- mediated STAT3 activation
is associated with the expected IL-6- mediated increase in SOCS3 expression,
along with other acute phase genes. Factors like SOCS play an important role in
the down-regulation of GH and GH signaling. Importantly, it is reported that
IL-6 inhibits hepatic GH signaling through up-regulation of SOCS3. As such, it
is possible that, in MIA placentas, maternal IL-6-induced STAT3 activation and
downstream sequelae lead to suppression of placental GH levels, disruption of
IGFI production and further consequences on maternal physiology, placental
function and fetal development. Altered placental physiology and release of
deleterious mediators to the fetus are important risk factors for the
pathogenesis of neurodevelopmental disorders. Placental IGFI in particular
regulates trophoblast function , nutrient partitioning and placental efficiency.
Moreover, altered IGFI levels are associated with intrauterine growth restriction
(IUGR) and abnormal development. Animal models of IUGR and intrauterine infection,
where the immune insult is confined to the uteroplacental compartment,
highlight the key role of placental inflammation in perinatal brain damage,
involving altered cortical astrocyte development, white-matter damage, microglial
activation, cell death and reduced effectiveness of the fetal blood–brain barrier.
In addition, adult pathophysiology is subject to feto-placental ‘‘programming’’,
wherein molecular changes that occur prenatally reflect permanent changes that
persist throughout postnatal life. Interestingly, placental responses to
maternal insults can potentiate sexually dimorphic effects on fetal development. Obstetric complications are
linked to schizophrenia risk and to the treatment responses of schizophrenic
individuals. Notably, a greater occurrence of placental trophoblast inclusions
was observed in placental tissue from children who develop autism spectrum
disorder (ASD) compared to non-ASD controls. Chorioamnionitis and other
obstetric complications are significantly associated with socialization and
communication deficitis in autistic infants. The characterization of placental pathophysiology
and obstetric outcome in ASD and schizophrenic individuals will be useful for
the identification of molecular mechanisms that underlie these disorders and
for potential biomarkers for early risk diagnosis. In addition to the observed
effects of IL-6 on placental physiology and its
downstream effects on fetal brain development and postnatal growth, direct
effects of IL-6 on the fetal brain are also likely. Maternal IL-6 can
potentially cross the placenta and enter the fetus after MIA. Furthermore, IL-6
mRNA and protein are elevated and STAT3 is phosphorylated in the fetal brain
itself following MIA, raising the obvious possibility that IL-6 acts directly
on the developing brain to influence astrogliosis, neurogenesis, microglial
activation and/or synaptic pruning. However, recall that the identification of
IL-6 as a critical mediator of MIA is based on maternal co-injection of poly(I:C)
and anti-IL-6 blocking antibody, in addition to experiments inducing MIA in
IL-6 KO animals. As such, in considering which pool(s) of IL-6 (e.g. maternal,
placental, fetal brain, fetal periphery) is the ‘‘critical mediator’’, it will
be important to understand the potential interaction between maternal IL-6 and
fetal brain IL-6 expression. While we believe that the endocrine changes triggered
by maternal-IL-6 signaling in the placenta reported here are important for
fetal growth, it will be crucial to assess the potential impact of these
placental changes on offspring behavior and neuropathology. We are currently
exploring the effects of MIA in targeted IL-6Ra KOs in order to tie tissue- and cell-specific IL-6 activity to the
manifestation of schizophrenia- and autism-related endophenotypes."
